My laboratory is involved in studies to genetically modify autologous lymphocytes to improve their anti-tumor activity. In 1990 we reported the first studies of gene transfer in humans which involved the adoptive transfer of TIL transduced with a marker gene encoding neomycin phosphotransferase. These studies suggested the possibility that genes could be inserted into lymphocytes to improve their anti-tumor efficacy. We have now made progress in this area by developing techniques for the high efficiency transduction of human lymphocytes. The genes encoding high affinity anti-tumor T cell receptors (TCR) that recognize antigens on melanomas and common epithelial cancers have been identified and clinical trials to use autologous T cells transduced with these TCRs have begun. In recent studies we have shown that up to 30% of patients with metastatic melanoma will achieve objective clinical cancer regressions when treated with their autologous lymphocytes that have been transduced with T cell receptors that recognized the MART-1 or gp100 melanoma antigens. T cell receptors have now been identified that recognize NY-ESO-1, MAGE-A3, and CEA epitopes. Chimeric antigen receptors have been developed that recognize CD19 cell surface antigens on B cell malignancies and the EGFRvIII mutation expressed on glioblastomas. Clinical trials are being performed to study the treatment of patients with a variety of cancer types using these transduced cells. Multiple patients treated with cells transduced with a chimeric receptor targeting CD19 have had substantial responses. 80% of patients treated have had objective responses in the absence of IL-2 administration. Using cells transduced with a TCR reactive with the NY-ESO-1 cancer testes antigen 10 of 19 melanoma patients and 10 of 15 synovial cell sarcoma patients have had objective responses.